Decoding tobacco-related oral cancer ecosystem by integrative approach

项目摘要 口腔癌的已知危险因素是吸烟和饮酒以及人乳头瘤病毒（HPV）感染。 烟草使用和HPV感染之间存在明显的相互作用。吸烟者的患病率明显高于 持续性口腔HPV感染是口腔癌的重要危险因素。吸烟的病人- 相关的口腔癌预后差。除了烟草对基因组DNA造成的明显损害外， 香烟烟雾暴露也显著影响免疫系统。近年来，免疫疗法已成为 口腔癌的一种有前途的治疗选择。程序性细胞死亡-1（PD-1）是目前临床上最常见的一种细胞凋亡蛋白， 已经显示在与其配体结合时抑制T细胞功能的重要检查点分子， PD-L1和PD-L2。Nivolumab和Pembrolizumab是最有效和安全的两种PD-1抑制剂 口腔癌的治疗方法虽然持续使用烟草的有害影响已被 多年来，烟草使用对肿瘤免疫微环境（TIME）的影响， 口腔癌中的免疫治疗功效研究很少。在这份提案中，我们将全面 通过综合多组学方法评估烟草对口腔癌生态系统的影响， 确定利用口腔癌特异性TIME的新型治疗剂，并开发口腔癌特异性 促进烟草相关癌症研究领域的门户网站。

PROJECT SUMMARY Known risk factors for oral cancers are tobacco and alcohol use and human papillomavirus (HPV) infection. There is a clear interaction between tobacco use and HPV infection. Smokers have a significantly higher rate of persistent oral HPV infection which is a significant risk factor to develop oral cancer. Patients with tobacco- related oral cancers have poor prognosis. Apart from the obvious damage tobacco causes to genomic DNA, cigarette smoke exposure also significantly impacts the immune system. Recently immunotherapy has become a promising therapeutic option in oral cancer. Programmed cell death-1 (PD-1) is one of the clinically significant checkpoint molecules that have been shown to suppress T-cell function upon binding to its ligands, PD-L1 and PD-L2. Nivolumab and pembrolizumab are the two PD-1 inhibitors with the most efficacy and safety data in management of oral cancer. While the detrimental effects of continued tobacco use have been established over the years, the effects of tobacco use in the tumor immune microenvironment (TIME) and immunotherapy efficacy in oral cancers are poorly investigated. In this proposal, we will comprehensively evaluate the tobacco-related effects on the oral cancer ecosystem through integrated multi-omics approaches, identify novel therapeutic agents leveraging the oral cancer-specific TIME, and develop an oral cancer specific web portal to advance the field in tobacco-related cancer research.